tbuckley/cabot-search huggingface dataset:
Recombinant factor VIII Fc fusion protein for first-time immune tolerance induction: final results of the verITI-8 study
Authors: Lynn Malec, An Van Damme, Anthony K. C. Chan, Mariya Spasova, Nisha Jain, Charlotte Sensinger, Jennifer Dumont, Stefan Lethagen, Manuel Carcao, Flora Peyvandi
Journal: Blood (2023)

Inhibitor development remains a major challenge in factor VIII (FVIII) replacement therapy. verITI-8 is the first prospective study of a recombinant FVIII Fc fusion protein (rFVIIIFc; efmoroctocog alfa) for first-time immune tolerance induction (ITI) in males with severe hemophilia A and high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL). In this single-arm, open-label, multicenter study, screening was followed by ITI (rFVIIIFc 200 IU/kg per day until tolerization or maximum of 48 weeks). Those who achieved ITI success entered a tapering period, returning to standard prophylaxis, and then entered follow-up. Primary end point was time to tolerization with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg), and half-life (t½) ≥7 hours within 48 weeks. Sixteen patients received ≥1 rFVIIIFc dose. Twelve (75%), 11 (69%), and 10 patients (63%), respectively, achieved negative inhibitor titers, an IR ≥66%, and a t½ ≥7 hours (ie, tolerance) within 48 weeks. Median times in weeks to achieve these markers of success were 7.4 (interquartile range [IQR], 2.2-17.8), 6.8 (IQR, 5.4-22.4), and 11.7 (IQR, 9.8-26.2), respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 1 reported ≥1 related TEAE (injection site pain). Nine patients experienced ≥1 treatment-emergent serious AE. No thrombotic events, discontinuations because of AEs, or deaths were reported during the study. As the first extended half-life rFVIII with prospective data in ITI, rFVIIIFc offered short time to tolerization with durable responses in almost two-thirds of patients and was well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT03093480.
Eldryd Hugh Owen Parry: cardiologist who founded the Tropical Health and Education Trust
Authors: Matt Limb
Journal: BMJ (2023)

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Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution
Authors: Alex A. Pollen, Umut Kilik, Craig B. Lowe, J. Gray Camp
Journal: Nature Reviews Genetics (2023)

Our ancestors acquired morphological, cognitive and metabolic modifications that enabled humans to colonize diverse habitats, develop extraordinary technologies and reshape the biosphere. Understanding the genetic, developmental and molecular bases for these changes will provide insights into how we became human. Connecting human-specific genetic changes to species differences has been challenging owing to an abundance of low-effect size genetic changes, limited descriptions of phenotypic differences across development at the level of cell types and lack of experimental models. Emerging approaches for single-cell sequencing, genetic manipulation and stem cell culture now support descriptive and functional studies in defined cell types with a human or ape genetic background. In this Review, we describe how the sequencing of genomes from modern and archaic hominins, great apes and other primates is revealing human-specific genetic changes and how new molecular and cellular approaches - including cell atlases and organoids - are enabling exploration of the candidate causal factors that underlie human-specific traits.
Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A
Authors: Pedro Gonzalez-Menendez, Ira Phadke, Meagan E Olive, Axel Joly, Julien Papoin, Hongxia Yan, Jérémy Galtier, Jessica Platon, Sun Woo Sophie Kang, Kathy L. McGraw, Marie Daumur, Marie Pouzolles, Taisuke Kondo, Stéphanie Boireau, Franciane Paul, David J Young, Sylvain Lamure, Raghavendra G Mirmira, Anu Narla, Guillaume Cartron, Cynthia E. Dunbar, Myriam Boyer-Clavel, Natalie Porat-Shliom, Valerie Dardalhon, Valerie S Zimmermann, Marc Sitbon, Thomas Dever, Narla Mohandas, Lydie M Da Costa, Namrata D. Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor
Journal: Blood (2023)
Targeting the immune microenvironment in Waldenström Macroglobulinemia via halting the CD40/CD40-ligand axis
Authors: Antonio Sacco, Vanessa Desantis, Jon Celay, Viviana Giustini, Fabio Rigali, Francesco D Savino, Michele Cea, Debora Soncini, Antonia Cagnetta, Antonio Giovanni Solimando, Deborah D'Aliberti, Silvia Spinelli, Daniele Ramazzotti, Camillo Almici, Katia Todoerti, Antonino Neri, Antonella Anastasia, Alessandra Tucci, Marina Motta, Marco Chiarini, Yawara Kawano, Jose-Al Martinez-Climent, Rocco Piazza, Aldo M Roccaro
Journal: Blood (2023)
The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53
Authors: Maria-Riera Piqué-Borràs, Zivojin Jevtic, Frederik Otzen Bagger, Jonathan Seguin, Rathick Sivalingam, Matheus Filgueira Bezerra, Amber Louwaige, Sabine Juge, Ioannis Nellas, Robert Ivanek, Alexandar Tzankov, Ute Moll, Oriano Valerio Cantillo, Ramona Schulz-Heddergott, Alexandre Fagnan, Thomas Mercher, Juerg Schwaller
Journal: Blood (2023)

The NFIA-ETO2 fusion is the product of a t(1;16)(p31;q24) chromosomal translocation, so far, exclusively found in pediatric patients with pure erythroid leukemia (PEL). To address the role for the pathogenesis of the disease, we facilitated the expression of the NFIA-ETO2 fusion in murine erythroblasts (EBs). We observed that NFIA-ETO2 significantly increased proliferation and impaired erythroid differentiation of murine erythroleukemia cells and of primary fetal liver-derived EBs. However, NFIA-ETO2-expressing EBs acquired neither aberrant in vitro clonogenic activity nor disease-inducing potential upon transplantation into irradiated syngenic mice. In contrast, in the presence of 1 of the most prevalent erythroleukemia-associated mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant clonogenic activity and induced a fully penetrant transplantable PEL-like disease in mice. Molecular studies support that NFIA-ETO2 interferes with erythroid differentiation by preferentially binding and repressing erythroid genes that contain NFI binding sites and/or are decorated by ETO2, resulting in a activity shift from GATA- to ETS-motif-containing target genes. In contrast, TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets. Collectively, our work indicates that NFIA-ETO2 initiates PEL by suppressing gene expression programs of terminal erythroid differentiation and cooperates with TP53 mutation to induce erythroleukemia.
Predictive value of staging PET/CT to detect bone marrow involvement and early outcomes in marginal zone lymphoma
Authors: Juan Pablo Alderuccio, Isildinha M. Reis, Jean L. Koff, Melissa C. Larson, Dai Chihara, Wei Zhao, Sara Haddadi, Thomas M. Habermann, Peter Martin, Jennifer R. Chapman, Christopher Strouse, Brad S. Kahl, Jonathon B. Cohen, Jonathan W. Friedberg, James R. Cerhan, Christopher R. Flowers, Izidore S. Lossos
Journal: Blood (2023)
Impact of the COVID-19 Pandemic on Cancer Screening Delays
Authors: Xiaochen Zhang, Mohamed I. Elsaid, Cecilia DeGraffinreid, Victoria L. Champion, Electra D. Paskett, Guy Brock, Chasity Washington, Amy K. Ferketich, Heather Hampel, Heather Aker
Journal: Journal of Clinical Oncology (2023)

To examine delays in cancer screenings during the COVID-19 pandemic.
Pembrolizumab Plus Chemotherapy in Squamous Non–Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study
Authors: Silvia Novello, Dariusz M. Kowalski, Alexander Luft, Mahmut Gümüş, David Vicente, Julien Mazières, Jeronimo Rodríguez-Cid, Ali Tafreshi, Ying Cheng, Ki Hyeong Lee, Alexander Golf, Shunichi Sugawara, Andrew G. Robinson, Balazs Halmos, Erin Jensen, Paul Schwarzenberger, M. Catherine Pietanza, Luis Paz-Ares
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report 5-year efficacy and safety outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier: NCT02775435 ). Eligible patients with previously untreated, metastatic squamous non–small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles. Primary end points were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five hundred fifty-nine patients were randomly assigned in the intention-to-treat population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281). The median time from random assignment to data cutoff was 56.9 (range, 49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. Toxicity was manageable. Among 55 patients who completed 35 cycles of pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC and is a standard-of-care first-line treatment option for metastatic squamous NSCLC regardless of programmed death ligand 1 expression.
Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study
Authors: Xi Ding, Wei-Jing Zhang, Rui You, Xiong Zou, Zhi-Qiang Wang, Yan-Feng Ouyang, Lan Peng, You-Ping Liu, Chong-Yang Duan, Qi Yang, Chao Lin, Yu-Long Xie, Si-Yuan Chen, Yong-Long Liu, Chen-Mei Gu, Ruo-Qi Xie, Pei-Yu Huang, Ming-Huang Hong, Yi-Jun Hua, Ming-Yuan Chen
Journal: Journal of Clinical Oncology (2023)

Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC).This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety.Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis.Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.
Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer
Authors: Antonela Merlotti, Benjamin Sadacca, Yago A. Arribas, Mercia Ngoma, Marianne Burbage, Christel Goudot, Alexandre Houy, Ares Rocañín-Arjó, Ana Lalanne, Agathe Seguin-Givelet, Marine Lefevre, Sandrine Heurtebise-Chrétien, Blandine Baudon, Giacomo Oliveira, Damarys Loew, Montserrat Carrascal, Catherine J. Wu, Olivier Lantz, Marc-Henri Stern, Nicolas Girard, Joshua J. Waterfall, Sebastian Amigorena
Journal: Science Immunology (2023)

Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non–small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8 + T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC.
Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements
Authors: Marianne Burbage, Ares Rocañín-Arjó, Blandine Baudon, Yago A. Arribas, Antonela Merlotti, Derek C. Rookhuizen, Sandrine Heurtebise-Chrétien, Mengliang Ye, Alexandre Houy, Nina Burgdorf, Guadalupe Suarez, Marine Gros, Benjamin Sadacca, Montserrat Carrascal, Andrea Garmilla, Mylène Bohec, Sylvain Baulande, Bérangère Lombard, Damarys Loew, Joshua J. Waterfall, Marc-Henri Stern, Christel Goudot, Sebastian Amigorena
Journal: Science Immunology (2023)

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer.
Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury
Authors: Sanjaya K. Sahu, Ayşe N. Ozantürk, Devesha H. Kulkarni, Lina Ma, Ruteja A. Barve, Linus Dannull, Angel Lu, Marick Starick, Ja’Nia McPhatter, Lorena Garnica, Maxwell Sanfillipo-Burchman, Jeremy Kunen, Xiaobo Wu, Andrew E. Gelman, Steven L. Brody, John P. Atkinson, Hrishikesh S. Kulkarni
Journal: Science Immunology (2023)

The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.
Endoscopic removal of an appendiceal foreign body using a disposable pancreaticobiliary imaging catheter
Authors: Zhaorong Tang, Daixing Chen, Jia Deng, Feng Ye, Hong Qiu, Xiaolong Du, Xiaojun Yang
Journal: Endoscopy (2023)

A 30-year-old man was admitted to our hospital following ingestion of a peg-like foreign body 6 days earlier. The patient reported no significant abnormalities. Physical examination showed a soft abdomen, without tenderness or rebound pain. Plain abdominal radiography revealed a peg-like object with high density in the right inferior abdomen ([Fig. 1]). Computed tomography confirmed that the object was at the appendiceal cavity, with no signs of perforation ([Fig. 2]). Endoscopic removal of the object was performed for this patient.
Endoscopic placement of a self-expandable metal stent for malignant small-intestine obstruction using a digital cholangioscope-guided approach
Authors: Li Zhong, Chan Qiu, Hang Yi, Song He, Suhua Wu, Chao Deng, Bo Ning
Journal: Endoscopy (2023)

For malignant gastrointestinal obstruction in inoperable patients, the self-expandable metal stent (SEMS) is a useful nonsurgical palliative treatment to improve patients' quality of life [1] [2] [3] [4]. The common method of intestinal stent placement is to navigate the guidewire through the narrow segment, which often takes a long time, and sometimes leads to stent placement failure because the guidewire cannot pass through the narrow segment. Here, we describe the successful endoscopic placement of an SEMS using a guidewire after a digital cholangioscope was used to pass through the narrow small intestine.
Hepatitis delta: Epidemiology to recent advances in therapeutic agents
Authors: Nehna Abdul Majeed, Benno Zehnder, Christopher Koh, Theo Heller, Stephan Urban
Journal: Hepatology (2023)

Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.
Recent advances in long-acting drug delivery systems for anticancer drug
Authors: Catarina Pacheco, Ana Baião, Tao Ding, Wenguo Cui, Bruno Sarmento
Journal: Advanced Drug Delivery Reviews (2023)

The use of systemic anticancer chemotherapy is intrinsically limited by its toxicity. Whether dealing with small molecules or biopharmaceuticals, after systemic administration, small doses fail to reach effective intratumoral concentrations, while high doses with significant tumor inhibition effects may also drive the death of healthy cells, endangering the patients. Therefore, strategies based on drug delivery systems (DDSs) for avoiding the systemic toxicity have been designed. Due to their ability to protect drugs from early elimination and control drug release, DDSs can foster tumor exposure to anticancer therapeutics by extending their circulation time or steadily releasing drugs into the tumor sites. However, approval of tailored DDSs systems for clinical use is minimal as the safety and the in vivo activity still need to be ameliorated by manipulating their physicochemical characteristics. During the last few years, several strategies have been described to improve their safety, stability, and fine-tune pharmaceuticals release kinetics. Herein, we reviewed the main DDSs, namely polymeric conjugates, nano or microparticles, hydrogels, and microneedles, explored for long-acting anticancer treatments, highlighting recently proposed modifications and their potential advantages for different anticancer therapies. Additionally, important limitations of long-acting anticancer therapies and future technology directions were also covered.
Neutrophil extracellular trap-associated carbamylation and histones trigger osteoclast formation in rheumatoid arthritis
Authors: Liam J O'Neil, Christopher B Oliveira, Xinghao Wang, Mario Navarrete, Ana Barrera-Vargas, Javier Merayo-Chalico, Rwan Aljahdali, Eduardo Aguirre-Aguilar, Philip Carlucci, Mariana J Kaplan, Carmelo Carmona-Rivera
Journal: Annals of the Rheumatic Diseases (2023)

Neutrophil infiltration into the synovial joint is a hallmark of rheumatoid arthritis (RA), a disease characterised by progressive bone erosion. However, the mechanisms by which neutrophils participate in bone destruction remain unclear. Carbamylation is a posttranslational modification linked to increased bone erosion in RA and we previously showed that carbamylation is present in RA neutrophil extracellular traps (NETs). However, it remains unclear whether NETs and their carbamylated protein cargo directly promote bone destruction and alter osteoclast biology.